Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol-carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. In addition, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals.
There are an increasing number of patents in the literature disclosing compounds which are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to DeVries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol. U.S. Pat. No. 4,824,843, issued to Hoefle et al. on Apr. 25, 1989, and the related U.S. Pat. No. 4,882,357, issued to Creger et al. on Nov. 21, 1989, disclose a series of substituted N-phenyl-2,2-dimethyl-5-aryloxypentanamides, which prevent the intestinal absorption of cholesterol in mammals by inhibiting ACAT. European Patent Application 325,397, filed by Ito on Jul. 26, 1989, discloses a series of compounds consisting of two N-cycloalkyl-N'-arylurea units linked at nitrogen by a dialkylphenyl unit, which are inhibitors of the ACAT enzyme. U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 1989, and the related European Patent Applications 335,374 filed by Trivedi on Mar. 30, 1988, and 386,487, filed by Trivedi on Feb. 9, 1989, disclose certain N-2,6-dialkyl- or N-2,6-dialkoxypheny-N'arylalkyl ureas as potent inhibitors of ACAT. European Patent Application 354,994, filed by Meguro and Ikeda on Feb. 21, 1990, discloses certain N-aryl-N'-quinolin-4-yl ureas as ACAT inhibitors. European Patent Application 370,740, filed by Jackson et al. on Nov. 21, 1988, discloses ACAT inhibitors similar in composition to those of DeVries (supra).
U.S. Pat. No. 4,900,744, issued to Billheimer, et al. on Feb. 13, 1990, discloses antihypercholesterolemic thioimidazoles of the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 independently are H, F, Cl, CF.sub.3, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms;
A is alkylene of 7-20 carbon atoms or an alkenyl residue thereof with no more than 2 double bonds; PA0 R.sup.3 is H, CH.sub.3 OR C.sub.2 H.sub.5 ; and PA0 n is 0, 1 or 2, such as 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid ethyl ester. PA0 R.sup.1 and R.sup.2 can also be taken together as ##STR3## where L is O, O(CH.sub.2).sub.m+1 O, or (CH.sub.2).sub.m where m is 0-4; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; PA0 R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sub.7 R.sub.8 or NCOR.sub.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sub.7 R.sub.8 or NCOR.sub.7 ; 2-, 3- or 4-pyridinyl, pyrimidinyl, or biphenyl; PA0 R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; PA0 R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.8 R.sup.9 or NCOR.sup.7 ; PA0 R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; PA0 X is S(O).sub.r, O, NR.sup.5, CH.sub.2 ; PA0 A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; PA0 Y is O, S, H.sub.2, NH; PA0 Z is NHR.sup.4, OR.sup.4, or R.sup.4 ; PA0 r is 0-2, PA0 R.sup.1 and R.sup.2 each represents hydrogen, halogen, alkyl, alkoxy, alkylthio, alkylamino, carboxy or alkoxycarbonyl; PA0 a and b are 0, 1, or 2; PA0 and Het represents a heterocyclic group containing from 5 to 7 ring atoms chosen from carbon, nitrogen, sulfur and oxygen atoms, and salts thereof. PA0 [DPIM] is: ##STR5## wherein R and R.sup.1 each represents hydrogen, halogen, alkyl or alkoxy; p is 0, 1, or 2; PA0 W represents alkylene; PA0 Y represents an optionally substituted 5- or 6-membered unsaturated ring containing 1 to 4 nitrogen atoms; PA0 k is 0, 1, or 2; PA0 Q is a straight or branched alkylene group; PA0 Z is a hydrogen or a substituent group; PA0 R.sup.7 is H, alkali metal ion, alkyl of 1 to 6 carbon atoms, or benzyl; and PA0 n is 0 to 10. PA0 R.sup.1, R.sup.2 and R.sup.3 independently are H, F, Cl, CH.sub.3, CH.sub.30, or CF.sub.3 ; PA0 R.sup.4 is H, Na, K, CH.sub.3, CH.sub.3 CH.sub.2, (CH.sub.3).sub.2 CH, CH.sub.3 (CH.sub.2).sub.2, or butyl; PA0 A is C(CH.sub.3).sub.2, CH(CH.sub.2).sub.m CH.sub.3, (CH.sub.2).sub.n, or (CH.sub.2).sub.n -.sub.2 CH(CH.sub.3); PA0 m is 0 to 8; and PA0 n is 2 to 10. PA0 R.sup.6 and R.sup.7 independently are H, OH, saturated or unsaturated alkyl, cycloalkyl, or hydroxyalkyl of 1 to 10 carbon atoms, ##STR11## R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently are H, F, Cl, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, and alkoxy of 1 to 3 carbon atoms, with the proviso that R.sup.8 and R.sup.9, R.sup.10 and R.sup.11, or R.sup.12 and R.sup.13 taken together represent methylenedioxy; PA0 R.sup.14 is alkyl of 1 to 2 carbon atoms; PA0 m and n taken together represent a whole number from to 9; PA0 p is 0 to 2; PA0 s is 0 to 2; and PA0 t is 0 or 2. PA0 R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl of 1 to 9 carbon atoms; PA0 R.sup.6 is alkyl, cycloalkyl, or hydroxyalkyl of 1 to 20 carbon atoms, H, alkali metal if X is --COO--, 1-phenethyl, or ##STR14## R.sup.7 is H, OH if X is --CONR.sup.7 --, or alkyl of 1 to 4 carbon atoms; R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are independently H, Cl, F, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, or alkoxy of 1 to 3 carbons, or R.sup.8 and R.sup.9 or R.sup.10 and R.sup.11 taken together represent methylenedioxy; PA0 X is a bond, O, OC(.dbd.O)O, C(.dbd.O)O, CONR.sup.7, OC(.dbd.O), or OC(.dbd.O)NR.sup.7 ; PA0 m and n taken together represent a whole number from 0 to 9; PA0 p is 0 to 2; PA0 s is 0 to 2; and PA0 t is 0 or 2. PA0 X.sub.1 is H, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino, or ##STR16## X.sub.2 is H, or when X.sub.1 is lower alkyl lower alkyl or halogen; k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; PA0 Y is O, S, or NH; PA0 E is NR.sup.2 ; PA0 R.sup.1 is H, lower alkyl or di-lower alkyl amino-lower alkyl; PA0 and R.sup.2 is H, nitro, or cyano. PA0 X.sub.1 and X.sub.2 may be H, lower alkyl, trifluoromethyl, hydroxyl, halogen, amino, or X.sub.1 and X.sub.2 and at least two of the atoms comprising A may form a further ring; PA0 k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; PA0 E is O, S, or NR.sup.2 ; PA0 R.sup.1 is H, lower alkyl, acyl, or dialkylamino-alkyl; PA0 and R.sup.2 is H, NO.sub.2, CN, alkansulphonyl or arenesulphonyl.
European Patent Application EP-A-372,445, filed by Billheimer et al. on Dec. 3, 1989, discloses compounds of formulae ##STR2## R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3- or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; or
or a pharmaceutically acceptable salt thereof.
These compounds are potent in vitro inhibitors of ACAT and are therefore potential antihypercholesterolemic agents.
International Application WO 91/09021 of Bridge et al., discloses compounds of the formula: ##STR4## wherein: A represents methylene or a group --CH.sub.2 --A'--CH.sub.2 --, wherein A' represents a direct bond, linear alkanediyl, alkenediyl or alkynediyl, hydroxymethylene, or optionally substituted phenylene;
These compounds are disclosed to be inhibitors of ACAT useful for the treatment of conditions such as atherosclerosis, hyperlipidemia, cholesterol ester shortage disease and atheroma in vein grafts.
International Application WO 91/10662 of Bridge et al., discloses compounds of the formula [DPIM]--S(O).sub.p --W-Y, wherein:
and pharmaceutically acceptable acid addition salts thereof.
Such compounds are disclosed to be inhibitors of ACAT.
International Application WO 91/13876 of Bridge et al., discloses compounds of the formula: ##STR6## wherein R.sup.1 is hydrogen or one or more substituents;
and pharmaceutically acceptable salts thereof.
Such compounds are disclosed to be inhibitors of ACAT.
U.S. Pat. No. 4,460,598, issued to Lautenschlager et al. on Jul. 17, 1984, discloses compounds of the formula: ##STR7## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently are H, F, Cl, Br, I, alkyl, alkoxy, or CF.sub.3, with the proviso that one or several of R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, or R.sup.5 and R.sup.6 taken together represent methylenedioxy;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed.
U.S. Pat. No. 4,654,358, issued to Lautenschlager et al. on Mar. 31, 1987, discloses compounds of the formula: ##STR8## wherein k is 0, 1, or 2,
The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic diseases is disclosed. German Laid Open Application No. DE 3504679, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR9## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or ##STR10## R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl of 1 to 9 carbon atoms;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
German Laid Open Application No. DE 3504680, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR12## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or ##STR13## R.sup.1 and R.sup.2 can be taken together with the carbon atoms in the 4 and 5 position of the imidazole ring to represent a carbocyclic five- or six-membered aromatic or partially hydrogenated ring which may be substituted by R.sup.8 or R.sup.9 ;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
Durant et al., U.S. Pat. No. 4,228,291, issued Oct. 14, 1980, teaches compounds of the formula: ##STR15## wherein: A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole, or 5,6,7,8-tetrahydro-imidazol[1,5-a]pyridine ring;
The compounds are said to be antihistamines of the H.sub.2 receptor blocking type, as well as having antiinflammatory activity.
White U.S. Pat. No. 4,413,130, Nov. 1, 1983, discloses histamine H.sub.2 receptor antagonists of the formula: ##STR17## wherein A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine;
There are no known literature references disclosing the imidazoles of this invention, their use as ACAT inhibitors, or their use to lower cholesterol or in the treatment of atherosclerosis.